Endothelin-2 in ovulation and luteal formation

Endocrinology cover imageEndothelin-2, a short 21 amino-acid peptide, is a product of the highly conserved Edn2 gene that we hypothesize to be involved in both ovulation and angiogenesis of the corpus luteum. It was originally identified in porcine aortic endothelial cells as a potent vasoconstrictor, one of the most potent discovered. In the last 25 years, Endothelin-2 has been found to be expressed in a variety of tissues. While attempting to identify new genes that might be critical for ovulation using a microarray exploration and subsequent protein analysis, Endothelin-2 was found to be quite highly expressed in the granulosa cells of rodent ovaries at the time of ovulation. Endothelin-2 mRNA expression spikes for a two hour period just prior to the time ovulation, before returning to the essentially nonexistent basal levels that are otherwise present throughout the ovary, regardless of cycle.

As a potent vasoconstrictive peptide, Endothelin-2 has been hypothesized to act on myoid cells in the ovary that are present around the granulosa cells of mature follicles. Contraction caused by Endothelin-2 could be a direct final trigger for ovulation. Supporting this, ovaries treated with Endothelin-2 strongly contract ex vivo, while those treated with Endothelin Receptor antagonist drugs ovulate fewer oocytes. As an ongoing follow up approach, I am now utilizing a transgenic mouse model in which Endothelin Receptors are absent only from the smooth muscle cells of the ovary, in the expectation that these mice will have difficulty ovulating, allowing the effect of Endothelin-2 to be pinpointed to those contractile cells

The Ko Laboratory specializes in transgenic animal models, and a second approach to look at the role of Endothelin-2 in ovulation using a mouse that globally lacked the Edn2 gene expression was also used. As expected, these mice ovulated fewer oocytes than control wild type mice, highlighting the overall importance of Endothelin-2. Interestingly, these mice all also lacked corpora lutea even if they successfully ovulated. The corpus luteum is a highly vascular structure that forms after ovulation and is necessary for progesterone synthesis and pregnancy maintenance. I am now focusing on generating mice that lack the Edn2 gene only in the ovary, under the belief that Edn2 is necessary for vessel formation through VEGF induction, endothelial cell expansion, MMP secretion, and/or monocyte invasion. I hope that this exploration can eventually be applied to either improve human and food animal fertility, or in the generation of novel contraceptive approaches.